Various MHC II haplotypes clearly differ in their ability to mount an encephalitogenic T-cell response [27, 28], which may relate to the signal strength they can possibly provide to the corresponding T cell. In context with the findings described in the previous paragraph, it appears likely, that besides molecular differences in the MI-503 price composition of MHC II, an enhanced expression level of the individual MHC II may independently increase the risk to trigger a proinflammatory autoimmune response. In

light of our novel preclinical finding, that an age-related upregulation of MHC II permits EAE development in adult mice, it will thus be instrumental to investigate whether expression levels of MHC II on blood-borne and CNS resident APCs may similarly vary throughout human development. Besides the presented developmental alterations in the innate immune cell compartment, several other age-associated mechanisms could contribute to the lower prevalence of CNS auto-immune disease at younger age. Mechanistically, completed myelination that occurs during early childhood could be a prerequisite for development of MS, as immune responses against myelin auto-Ags [29, 30] may be required for its initiation. Studies in EAE

indeed suggest that a relative lack of CNS myelination in immature brain and spinal cord may contribute click here to relative EAE resistance in immature rodents [31, 32]. However, incomplete CNS myelination is unlikely to explain the results of our study; first, CNS myelination in mice is completed at the age of 3 weeks [33], when in our hands mice were still entirely resistant to EAE. Second, and probably most important, protection from EAE development was associated with the inability of younger mice to generate a proinflammatory autoreactive T-cell response following an active EAE induction protocol. This insufficiency cannot be explained by any effect within the CNS including lack of myelination and instead points

toward an immaturity of the immunological synapse as plausible explanation. While we present one immunological Galeterone mechanism by which the low incidence and prevalence of MS in infancy could be determined, it is evident that other factors have to be considered as well. Besides MHC II-dependent development of CD4+ T cells, MHC I-restricted immune responses mediated by CD8+ T cells may play a similarly critical role in pathogenesis of CNS autoimmune diseases. Several studies indicate that CD8+ T cells may also participate as effector cells in EAE induction [34, 35]. In MS, clonally expanded CD8+ T cells accumulate within the CNS [36, 37]; in vitro, CD8+ T cells can kill oligodendrocytes [38] and neurons [39]. These findings are clearly suggestive of a pathogenic role of CD8+ T cells in CNS autoimmune disease.